Immune Enhancement and Therapy of Cancer

描述(由申请人提供)： 这项MMHC联盟的提案将涉及致癌的免疫生物学，特别是与器官特异性癌症的发生机制有关的三个关键问题，以及旨在治疗或预防癌症的策略，正如几个人类癌症基因工程小鼠模型所揭示的那样，并将在这些模型中进行研究。财团团队的目标集中在： I)阐明免疫增强的细胞和分子机制，即先天和后天免疫系统的细胞被招募来渗透肿瘤病变，其中它们被证明能够在功能上促进肿瘤进展，部分是通过激活血管生成和放大肿瘤细胞生长； Ii)确定在某些小鼠模型中明显存在的对T细胞炎症和实体瘤杀伤的隐性屏障的分子基础，并进一步评估其一般性；以及 3)改进在器官特异性致癌的完全免疫活性模型中诱导有效T细胞免疫疗法的策略，既评估并寻求绕过免疫增强和炎症屏障对疗效的潜在干扰。 该联盟团队将在选定的一组器官特异性癌症--乳腺癌、子宫颈癌和胰岛癌--中调查这些相互关联的肿瘤免疫生物学方面的规则和表现。该小组将询问免疫增强和炎症屏障是否是这些器官癌变的癌前阶段和新生肿瘤阶段的因素，以及/或者是良好实体肿瘤的持续生长和进展的因素。实验设计将揭示免疫增强和炎症屏障是否随着器官位置和进展阶段的不同而变化，并提供对这些参数影响肿瘤免疫治疗成功的可能性的洞察。通过结合免疫增强或炎症屏障的基于机制的干扰来提高T细胞免疫对抗乳腺癌前病变或恶性病变的疗效的前景将在临床前试验中进行评估。一个由肿瘤生物学家和免疫学家组成的非凡小组已经聚集在一起，以他们的集体支持和互补的专业知识来追求这些战略目标。

DESCRIPTION (provided by applicant): This MMHC consortium proposal will address the immunobiology of carcinogenesis, in particular three critical issues related to mechanisms by which organ specific cancers develop, and to strategies aimed at treating or preventing cancer, as revealed by and to be studied in several genetically engineered mouse models of human cancer. The goals of the consortium team center upon: i) elucidating the cell and molecular mechanisms of immune enhancement, whereby cells of the innate and acquired immune system are recruited to infiltrate neoplastic lesions, wherein they have been shown to be capable of functionally enhancing neoplastic progression, in part by activating angiogenesis and amplifying tumor cell growth; ii) identifying the molecular basis of implicit barriers to T cell inflammation and killing of solid tumors that are evident in certain mouse models and further assessing its generality, and iii) refining strategies for induction of efficacious T cell immunotherapies in fully immunocompetent models of organ-specific carcinogenesis, both assessing and seeking to circumvent the potential interference with efficacy by immune enhancement and inflammatory barriers. The consortium team will investigate the regulation and manifestation of these interrelated facets of tumor immunobiology in a select group of organ-specific cancers, of breast, cervix, and pancreatic islet. The group will ask whether immune enhancement and inflammatory barriers are factors for premalignant and nascent tumor stages of carcinogenesis in these organs, and/or for the continuing growth and progression of well established solid tumors. The experimental designs will reveal whether immune enhancement and inflammatory barriers vary as a function of organ site and stage of progression, and provide insight into the possibility that these parameters can impact upon the success of tumor immunotherapy. The prospects for improving the efficacy of T cell immunity against either premalignant or malignant lesions in breast, cervix, and pancreas by combining mechanism-based disruptions in immune enhancement or inflammatory barriers will be assessed in preclinical trials. A remarkable group of tumor biologists and immunologists has been assembled to pursue these strategic goals with their collectively enabling and complementary expertise.